Day 2: Wednesday, December 7, 2011
Summary of Bisphospohonate studies presented
Bisphosphonates prevent the loss of bone mass and strengthen the bone. In addition to being used to treat osteoperosis, bisphospohonates have been studied for treating metastatic breast cancer on the theory that they make bones less hospitable for tumor gowth. Several trials studying this use of bisphosphonates were presented at this year’s SABCS symposium.
In breast cancer, bisphosphonates are being investigated for their role in (a) protecting bone health due to negative effects of endocrine therapy, (b) preventing bone metastasis and (c) improving disease free survival (and hopefully overall survival).
Michael Gnant: academic trial of adjuvant zoledronic acid
Long term follow up of the Austrian Breast and Colorectal Cancer Study Group (ABSCG) found that the bisphosphonate, zoledronic acid (marketed by Novartis under Zomera or Zometa) may be a new standard of care for premenopausal breast cancer patients with early stage ER+ tumors who are receiving hormone therapy (tamoxifen or Arimidex).
Background: Bisphosponates are an established standard of care for bone metastasis and can be used to treat early breast cancer, as well as reduce the risk of some cancers in men and women. The hypothesis is that bisphosphonates address micro bone metastasis.
For this study, 1803 premenopausal patients were recruited in Austria between 1999-2006. The study looked at early stage breast cancer (with ¾ of the tumors less than 2cm in size and 2/3 node negative). Median age of participants was 45 years. Women were treated for 3 years. And the study followed participants for 84 months on average. Participants were randomized into four groups:
Tamixifen + zoledronic acid
Anastrozole + zoledronic acid
Regardless of which estrogen suppressor was used, the zoledronic acid group showed a 28% reduction in recurrence with the treatment of this bisphospohonate. In addition to reducing recurrence, there was also a reduction in mortality rate. Overall survival was high in both groups and the study found that zoledronic acid improves overall survival compared with endocrine therapy alone. Women over 40 receiving zolodronic acid had an overall survival rate of 97.5% at 5 years and 95.5% at 7 years. ER+ breast cancers continue to have a risk of recurrence after these benchmarks.
Sub group analysis showed that there was disease free benefit for all groups but the greatest benefits were for women over age 40. There was less benefit for women under 40, for whom ovarian suppression may not be complete. For those women over 40 with complete ovarian suppression, researchers found maximum efficacy of the bisphosphonate: this group saw a one-third reduction in relapse and a 31% decrease in death. Clearly there is a need to understand menopausal status and the question emerges why 40 was chosen for the age cut-off of the subset analysis.
Serious adverse effects were covered quickly in the presentation (per usual) but they included increased bone pain and pyrexia.
Treatment of premenopausal women with breast cancer with ER+ breast cancer with this combination of endocrine therapy and bisphosphonates has the potential to help women avoid chemotherapy and achieve more than 95% 7 year overall survival.
In summary, this study looked at patients with fairly good prognosis and met the primary and secondary endpoints of both disease free survival and overall survival. All women receiving zolodronic acid in the study saw these benefits but age matters. The efficacy of this bisphosphonate is best in women over 40 with complete ovarian suppression, suggesting the need to deprive tumors of estrogen and bone growth factors.
ZO-FAST, presented by Dr De Boer: Long term survival among post menopausal women
This study investigated the effects of bone health with the timing for use of zoledronic acid with the aromatase inhibitor, Letrozole. Secondary endpoints included disease free survival. This group of women was more than 10 years older on average than the women in the ABCSG-12 study, with the median age just under 60 in both groups. There were two arms:
one received zoledronic acid at the same time as letrozole; the other received delayed zoledronic acid after treatment with letrozole. Both groups were balanced with regard to bone health.
The presenter focused on the secondary endpoints of the study and an unplanned subset analysis that is interesting in light of the ABCSG-12 and a subset of the AZURE trials.
The study found that there was benefit to immediate, as opposed to delayed, use of zoledronic acid when it comes to disease free survival but as this was not the primary aim of the study, these findings were not statistically significant. There was a 35% improvement in disease free survival at five years, with an absolute difference of 3.6% (91.9% vs 88.3% respectively).
After conducting an unplanned subset analysis, of the recently versus truly menopausal patients, there was additional evidence that zoledronic acid performs best in a very low estrogen environment among truly menopausal women. While this may be clinically important these findings are based on unplanned analysis and are insuficient to support as standard of care in postmenopausal women.
Similar to the disease free survial results found by the ABCSG-12 and a subset of the AZURE trial, the ZO-FAST data suggests that zoledronic acid is most effective in a low-estrogen environment.
Serious toxicity includes osteonecrosis of jaw—all three of these cases occurred in the immediate zoledronic acid group.